Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive disability, afflicting 1 in every 800 live births. Importantly, the cause(s) of the cognitive disability in DS have not yet been uncovered. Our group has been studying the Ts65Dn mouse model of DS which has triplication of 184 of the 364 genes triplicated in DS. These mice have a large number of DS- relevant phenotypes, including cardiac and craniofacial defects as well as spatial learning/memory and motor abnormalities, the latter two of which have been principally measured in adult animals. We now report two major developmental forebrain phenotypes in Ts65Dn which precede these neurological deficits: 1) a dorsal forebrain abnormality which results in under-production of excitatory neurons and 2) a ventral forebrain defect which results in over-production of inhibitory interneurons. Together, these defects substantially shift the excitatory:inhibitory neuron ratio in Ts65Dn;we hypothesize that this is the primary cause for cognitive dysfunction in Ts65Dn/DS. Through a comprehensive set of experiments on cell proliferation, neural differentiation, gene expression and neuronal electrophysiology, we uncovered that two specific triplicated genes (the structurally linked transcription factors Olig1 and Olig2) cause the ventral Ts65Dn forebrain phenotype;we rescued the inhibitory defect in the embryonic and adult brain at the cellular and electrophysiological levels by generating Ts65DnOlig1/2? animals (reducing Olig1 and Olig2 genes from 3 to 2 alleles within the Ts65Dn background). In this period of study, we will determine whether Olig1/2 triplication influences the learning/memory and synaptic plasticity defects in Ts65Dn and investigate the role of the Dyrk1a minibrain gene in the (dorsal) excitatory neuron deficit in Ts65Dn. PUBLIC HEALTH RELEVANCE: Down syndrome is the most common genetic disorder resulting in mental retardation and it afflicts approximately 384,000 Americans (1:800). As such, the development of therapies for cognitive ability is critical for improving quality of life of patients and their families. In this project, we are discovering which triplicated genes lead to altered brain development and function in the Ts65Dn mouse model of Down syndrome. By reducing the dosage of three triplicated genes implicated in early brain development, this work will identify the gene targets, describe how their over-expression changes brain development and lead to prenatal and postnatal strategies for cognitive therapy.